The SLE-associated TREX1-P212fs mutation disrupts ER association leading to type I interferonopathy

The TREX1 gene encodes a highly efficient DNA exonuclease that plays an important role in maintaining DNA homeostasis in the cytoplasm. TREX1 mutations lead to a spectrum of type I interferonopathies that are characterized by systemic inflammation, high blood levels of autoantibodies, and spontaneously activated immunity. The TREX1-P212fs mutation is thought to be linked to systemic lupus erythematosus (SLE). Here, we analyzed the functions of 20 TREX1 mutants and found that the TREX1-P212fs mutant was able to reduce DNA enzyme activity and missed endoplasmic reticulum localization. Mouse-derived in situ Trex1 models of transcoding mutations have not been reported. We successfully constructed Trex1-P212fs mice by CRISPR-Cas9 technology. Trex1^{P212fs/P212fs} mice exhibit systemic inflammation, lymphocytosis, vasculitis, and kidney disease. The excessive autoantibody production was also present in these mice. We further demonstrated that TREX1 (1-212) protein lost its interaction with RPN1, the subunit that makes up the oligosaccharyl transferase (OST) complex. These data suggest an important role of TREX1-C-terminal association with the endoplasmic reticulum in inducing immune activation and the Trex1-P212fs model may provide theoretical support for a better understanding of SLE treatment and defense.